Researchers discover key gene that promotes development of common kidney cancer
February 11, 2016
The HDAC inhibitor used in this study is currently being examined in clinical trials for other cancers. It is similar to HDAC inhibitors that are already approved by the Food and Drug Administration for use in cutaneous T cell lymphoma. Dr. Cooper says that data from this study proves that these drugs synergize to restore GATA3 function, but they still need to be tested in kidney cancer animal models to provide a rationale for proceeding to a cancer clinical trial in kidney cancer.
This study results from a 2003 discovery by Dr. Copland and his team that the loss of T-RIII plays a critical role in kidney cancer cell growth. T-RIII appears to be a tumor suppressor gene that blocks tumor growth. Although it is well known that the ligand, transforming growth factor beta (TGF--) binds T-RIII on the cell membrane, T-RIII's growth inhibitory activity is TGF-- independent, another novel finding.
They found that T-RIII was not expressed in patient ccRCC tissues that they examined; in the laboratory, when it was re-expressed in human ccRCC cell lines, the kidney cancer cells died. "We believe T-RIII is a tumor suppressor which is lost in a number of cancers," says Dr. Copland. "In ccRCC, every patient tumor that we have examined has lost the expression of this receptor as well as GATA3."
"Interestingly, the T-RIII gene is regulated, not by one, but two different promoters. Our team is the first to clone the human T-RIII promoters which allowed us to delete regions and discern how T???RIII expression is regulated," explains Dr. Cooper. They eventually located a region that led to the discovery that GATA3 positively regulates T???RIII expression in normal renal cells. This is the first transcription factor discovered to positively regulate the human T-RIII gene.
"Now that we understand why T-RIII is not expressed in kidney cancer, we can potentially turn the gene back on by reactivating GATA3 using methyltransferase and HDAC inhibitors," Dr. Copland says.
Source: Mayo Clinic